Autism Spectrum Disorders (ASDs) are a group of related neurodevelopmental syndromes defined by social communication deficits and by restricted and repetitive behaviors. The public health burden is enormous, with an estimated cost of $35 billion in the U.S alone. Behavioral approaches are currently the mainstay of treatment; options for somatic therapies remain extremely limited. A new generation of more effective treatments will require a far deeper understanding of the pathobiology of ASD. In addition, while there has been significant recent progress in clarifying the genomic architecture of autism, only a small number of the hundreds of genes and genomic regions thought to be involved in ASD have so far been identified. The current proposal focuses on discovering additional rare recessive mutations leading to autism via the study of consanguineous families from Egypt and Turkey. The project leverages a long-standing collaboration between the Gunel and State labs, which have independently and collectively demonstrated the productivity of homozygosity mapping and whole exome sequencing for a range of developmental disorders including autism. Our long-term goal is to make use of genetics to identify therapeutic targets in ASD while contributing to translating such findings to clinical practice. Our hypothesis is that th discovery of additional rare recessive, highly penetrant ASD mutations in consanguineous families will advance the understanding of molecular mechanisms; that these will show overlap with the emerging picture of the genetic architecture and biology of idiopathic ASD in outbred populations, and that, combined, these advances will lay the foundation for the development of novel, rational, and more efficacious treatments. Therefore, we focused on 3 specific aims: 1) To expand our current cohort of consanguineous ASD families with an additional 250 carefully diagnosed ASD kindreds from Egypt and Turkey, 2) To identify novel, rare, highly penetrant genetic variants that contribute to ASD by employing homozygosity mapping and whole-exome sequencing in 384 ASD subjects and parents; and 3) To search for clustering of these variants among unrelated families as well as to evaluate the overlap in risk loci for inbred versus outbred ASD populations, cross- referencing findings from these Middle Eastern families with data from the Simons Simplex Collection (SSC), which we have been studying for the past 5 years and to evaluate the identified homozygous variants with reference to ASD-associated developmental co-expression networks using high confidence ASD genes discovered in outbred families. Overall this proposal is aimed at advancing the understanding of the genetics and biology of ASD in the interests of identifying novel approaches to diagnosis, and therapeutic development.